The active metabolite of vitamin D.sub.3 (cholecalciferol) is 1,25-dihydroxycholecalciferol (1,25-(OH).sub.2 D.sub.3). Parathyroid hormone (PTH) is produced by the parathyroid glands. The release of PTH is activated by a decrease in blood Ca.sup.2+ level below normal. The production of 1,25-(OH).sub.2 D.sub.3 in the kidney requires the presence of 1-hydroxylase whose formation is induced by PTH. Since PTH acts upon the kidney to increase the production of 1,25-(OH).sub.2 D.sub.3, it appears that a negative feedback system could operate to regulate PTH secretion. The absorption of calcium from the intestine into the blood requires, for transport, a calcium-binding protein (CaBP). Synthesis of CaBP is activated by 1,25-(OH).sub.2 D.sub.3. Both PTH and 1,25-(OH).sub.2 D.sub.3 are active in the increase of blood Ca.sup.2+ concentration by increasing resorption of calcium from bone. The interrelationship of blood Ca.sup.2+ concentration, PTH levels and 1,25(OH).sub.2 D.sub.3 levels is shown in FIG. 1 which is published in Rollinson et al "Mineral Nutrients" , in Kirk-Othmer Encyclopedia of Chemical Technology, 3rd edition, John Wiley & Sons, New York, vol. 15, page 585, 1981. In this figure, CC is cholecalciferol (vitamin D.sub.3), HCC is hydroxycholecalciferol, DHCC is 1,25-(OH).sub.2 D.sub.3 and NADPH is protonated nicotinamide-adenine dinucleotide phosphate.
Secondary hyperparathyroidism is a universal complication of chronic renal insufficiency (cf. Reiss et al., Trans. Assoc. Am. Physicians, 81:104-115, 1968; Arnaud, Kidney Int. 4:89-95, 1973). In severe renal insufficiency, the lack of 1,25(OH) becomes a factor in maintaining the hypersecretion of PTH.
The suppressive effect of 1,25-(OH).sub.2 D.sub.3 on pTH secretion has led to its use for treatment of secondary hyperparathyroidism. Administration of 1,25-(OH).sub.2 D.sub.3 was found to lower PTH levels in hemodialysis patients more effectively than calcium, even when both substances raised ionized calcium to the same degree (Slatopolsky et al., J. Clin. Invest., 74:2136-2143, 1984). Parathyroid cells from patients with secondary hyperparathyroidism are less sensitive to the suppressive effects of calcium (Brown et al., J. Clin. Endocrinol. Metab., 54:172-179, 1982). Furthermore, it appears that intravenous 1,25-(OH).sub.2 D.sub.3 treatment of renal failure patients shifts the set point for calcium toward more normal values (Delmez et al., J. Clin. Invest., 1989, in press).
Although 1,25-(OH).sub.2 D.sub.3 is now commonly used to treat hyperparathyroidism associated with renal failure, and particularly patients undergoing renal dialysis, its prolonged use is precluded in some cases by hypercalcemia. This is compounded by the fact that calcium carbonate is currently the preferred compound for binding of intestinal phosphorus, which is mandatory before vitamin D is administered to uremic patients. Calcium carbonate is the phosphate-binder of choice since phosphate binders containing aluminum frequently induce aluminum accumulation, with its well known deleterious effects. Unfortunately, the simultaneous administration of large doses of calcium carbonate and 1,25-(OH).sub.2 D.sub.3 frequently induces severe hypercalcemia, thus precluding the administration of therapeutic doses of 1,25-(OH).sub.2 D.sub.3.
More recently, the suppressive action of 1,25-(OH).sub.2 D.sub.3 on parathyroid hormone synthesis and secretion has been better defined. It has been suggested that 1,25-(OH).sub.2 D.sub.3 can suppress PTH directly, independent of calcium (Chertow et al, J. Clin. Invest., 72:668-678, 1975). Primary cultures of bovine parathyroid cells have been used to demonstrate that 1,25-(OH).sub.2 D.sub.3 inhibits release of PTH (Cantley et al., Endocrinology, 117:2114-2119, 1985; Chan et al, Calcif. Tissue Int., 38:27-32, 1986), decreases the levels of pre-proPTH mRNA (Silver et al, Proc. Natl. Acad. Sci. USA, 82:4270-4273, 1985), and blocks transcription of the PTH gene (Russell et al, Endocrinology, 119:2864-2866, 1986). This inhibition of transcription in vivo may not be secondary to an increase in serum calcium (Silver et al, J. Clin. Invest., 78:1296-1301, 1986). The close correlations between PTH release and the decrease in pre-proPTH mRNA, and the lack of an acute effect of 1,25-(OH).sub.2 D.sub.3 indicates that 1,25-(OH).sub.2 D.sub.3 acts at the transcriptional level. Furthermore, since physiological concentrations (10.sup.-11 M) of 1,25-(OH).sub.2 D.sub.3 in the culture medium suppressed release and synthesis of PTH, it seems likely that conditions in which 1,25-(OH).sub.2 D.sub.3 levels are abnormally low, e.g., renal failure, would lead to increases in serum PTH.
A number of analogs of 1,25-(OH).sub.2 D.sub.3 have been synthesized that have little calcemic activity but retain the ability to differentiate myeloid leukemia cells. 24-Homo-1,25-(OH).sub.2 D.sub.3 can differentiate HL-60 cells without increasing serum calcium when administered to vitamin D-deficient rats (Ostrem et al, Proc. Natl. Acad. Sci. USA, 84:2610-2614, 1987). Similar differential activity occurs with MC903, a 1,25-(OH).sub.2 D.sub.3 analog with a cyclopropyl group at the end of the side chain (Binderup et al, Bioch Pharmacology, 37:889-895, 1988). Furthermore, 22-oxa-1,25-(OH).sub.2 D.sub.3, also known as 22-oxa-calcitrol or OCT, has been shown to differentiate HL-60 with very low bone calcium mobilizing activity in vitro (Abe et al, FEBS Lett., 226:58-62, 1987). This compound also has no calcemic activity in vivo (Murayama et al, Chem. Pharm. Bull., 34: 4410-4413, 1987). Analogs including OCT are described in EP 0 184 112. There have been no reports to date as to the ability of any non-calcemic analog of 1,25-(OH).sub.2 D.sub.3 to emulate the activity of 1,25-(OH).sub.2 D.sub.3 in regulation of hyperparathyroidism.
Because of the known interrelationship among serum Ca.sup.2+, PTH and 1,25-(OH).sub.2 D.sub.3 levels, because of the unknown effects on PTH production caused by varying the structure of the 1,25-(OH).sub.2 D.sub.3 molecule, and because of the lack of any evidence correlating myeloid leukemia cell differentiation ability of 1,25-(OH).sub.2 D.sub.3 analogs with their effect on PTH transcription, there is no predictability as to the ability of any given analog of 1,25-(OH).sub.2 D.sub.3 to affect hypersecretion of PTH. Furthermore, since the action of 1,25-(OH).sub.2 D.sub.3 is mediated by a cellular receptor that is believed to be identical in all tissues, and since OCT binds to the chick intestinal receptor fourteen times less avidly than 1,25-(OH).sub.2 D.sub.3 (Murayama et al, 1987, supra) and is less active in raising serum calcium, the equivalent activity of OCT and 1,25-(OH).sub.2 D.sub.3 in parathyroid glands is surprising and would not have been predicted.